Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
Department of General Surgery, the Affiliated Hospital of Yangzhou University Medical School, Yangzhou 225001, China.
Int J Biol Sci. 2018 Jun 3;14(9):1033-1040. doi: 10.7150/ijbs.25589. eCollection 2018.
Kupffer cells (KCs) contribute to liver fibrosis resolution by production of a large spectrum of matrix metalloproteinases (MMPs). MMP9 is a major MMP expressed by KCs. However, its role in liver fibrosis resolution remains unclear. In this study, rodent liver fibrosis was induced by intraperitoneal thioacetamide (TAA) and the resolution process was initiated by TAA withdrawal. The role of KC-derived MMP9 in fibrolysis was investigated by adoptive transfer of KCs with or without MMP9 following their depletion. The levels of serum alanine aminotransferase (ALT) and hepatic cytokines were measured during fibrosis regression. The mRNA levels of MMPs and tissue inhibitor of metalloproteinases (TIMPs) were analyzed as well. It was found that removing KCs delayed fibrosis resolution. Adoptive transfer of KCs from WT animals promoted liver fibrosis resolution, compared with transfer of KCs from MMP9-/- mice. Depletion of KCs also resulted in prolonged liver wound healing, which was reversed partially by transferred KCs from either WT or MMP9-/- mice. Likewise, the absence of KCs led to reduction in MMPs mRNA levels and elevation in TIMPs mRNA levels. The expression patterns of MMPs or TIMPs were restored by adoptive transfer of the wild-type but not MMP9-/- KCs. In addition, liver fibrosis resolution was accelerated in MMP9-/- mice by adoptive transferred KCs from WT animals, compared to the KCs from MMP9-/- mice. Overall, KC-derived MMP9 plays a critical role in fibrosis resolution, which might serve as the foundation for developing anti-fibrosis therapy.
枯否细胞（KCs）通过产生大量基质金属蛋白酶（MMPs）促进肝纤维化的解决。MMP9 是 KCs 表达的主要 MMP。然而，其在肝纤维化解决中的作用尚不清楚。在这项研究中，通过腹腔注射硫代乙酰胺（TAA）诱导啮齿动物肝纤维化，并通过 TAA 撤药启动解决过程。通过耗尽 MMP9 后或不耗尽 MMP9 时进行 KCs 的过继转移，研究了 KC 衍生的 MMP9 在纤维溶解中的作用。在纤维化消退过程中测量了血清丙氨酸氨基转移酶（ALT）和肝细胞因子的水平。还分析了 MMPs 和金属蛋白酶组织抑制剂（TIMPs）的 mRNA 水平。结果发现，去除 KCs 会延迟纤维化的解决。与从 MMP9-/- 小鼠转移的 KCs 相比，从 WT 动物转移的 KCs 促进了肝纤维化的解决。KCs 的耗竭也导致肝脏伤口愈合延长，这部分被 WT 或 MMP9-/- 小鼠来源的转移 KCs 逆转。同样，KCs 的缺失导致 MMPs mRNA 水平降低和 TIMPs mRNA 水平升高。通过过继转移野生型而不是 MMP9-/- KCs，恢复了 MMPs 或 TIMPs 的表达模式。此外，与从 MMP9-/- 小鼠转移的 KCs 相比，在 MMP9-/- 小鼠中，通过过继转移来自 WT 动物的 KCs 加速了肝纤维化的解决。总体而言，KC 衍生的 MMP9 在纤维化解决中起着关键作用，这可能为开发抗纤维化治疗奠定基础。
